Liu Wei, Xin Yexin, Sun Mengyu, Liu Chenlong, Yin Xiangrong, Xu Xiaofei, Xiao Yilei
Shandong First Medical University, Jinan, Shandong 250117, China; Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shangdong 252000, China.
Department of Neurosurgery, Liaocheng People's Hospital, Liaocheng, Shangdong 252000, China; School of Clinical Medicine, Shandong Second Medical University, Weifang, Shangdong 261000, China.
J Stroke Cerebrovasc Dis. 2025 Apr;34(4):108251. doi: 10.1016/j.jstrokecerebrovasdis.2025.108251. Epub 2025 Jan 27.
Previous observational studies have suggested a potential association between heart rate variability (HRV) and cerebrovascular disease. However, a causal relationship between the two has not yet been established.
The objective of this study was to determine the causal relationship between heart rate variability (HRV) and stroke through a two-sample Mendelian randomization analysis.
Three genetic predictive traits of heart rate variability standard deviation of the normal-to-normal interbeat intervals (SDNN), the root mean square of the successive differences of interbeat intervals (RMSSD), and the peak-valley respiratory sinus arrhythmia or high-frequency power (pvRSA/HF) were collected from publicly available genome-wide association studies (IEU Open GWAS). Additionally, stroke (STROKE) and its sub-types: ischemic stroke (IS), cardioembolic stroke (CES), small vessel stroke (SVS), large artery stroke (LAS), lacunar stroke (LS), and intracerebral hemorrhage (ICH)were also from this database. Two-sample Mendelian randomization and various sensitivity analyses were employed to explore the causal relationship between HRV and stroke and its sub-types. Inverse-variance weighted (IVW) was the primary method via which Mendelian randomization (MR) was conducted, and for the causal estimates determined by IVW, a series of sensitivity analyses were performed to assess the reliability of the results. (i) Four additional MR methods that complement IVW were utilized; (ii) Cochran's Q-test was employed for assessing heterogeneity; (iii) the MR-Egger's intercept test and MR-PRESSO global test were applied to assess the level of multivariate validity, and (iv) the "leave-one-out" method was utilized to assess stability.
Two of the genetically predictive traits of HRV (standard deviation of the normal-to-normal interbeat intervals [SDNN]) and (the peak-valley respiratory sinus arrhythmia or high-frequency power [pvRSA/HF]) were associated with IS (OR 0.63,95 %CI 0.42-0.95, P = 0.03), (OR 0.84, 95 %CI: 0.72-1.00; P = 0.04), and LAS (OR 135.93, 95 %CI: 7.19-2569.22; P = 0.05), (OR 1.42, 95 %CI: 1.02-1.98; P = 0.04) were significantly correlated in addition to (pvRSA/HF) and LS (OR 0.84, 95 %CI: 0.72-1.00; P = 0.04) were also causally associated. Neither was causally associated with other sub-types of stroke or hemorrhagic stroke. Another genetically predictive trait of HRV (the root mean square of the successive differences of interbeat intervals [RMSSD]) was not found to be significantly associated with stroke, its subtypes, or Intracerebral hemorrhage.
This study provides genetic evidence supporting the causal effects of HRV (SDNN) on ischemic stroke (IS) and large artery stroke (LAS), as well as (pvRSA/HF) on ischemic stroke (IS), large artery stroke (LAS), and lacunar stroke (LS).
以往的观察性研究表明心率变异性（HRV）与脑血管疾病之间可能存在关联。然而，两者之间的因果关系尚未确立。
本研究的目的是通过两样本孟德尔随机化分析确定心率变异性（HRV）与中风之间的因果关系。
从公开的全基因组关联研究（IEU Open GWAS）中收集心率变异性的三个遗传预测指标，即正常心跳间期标准差（SDNN）、心跳间期连续差值的均方根（RMSSD）以及峰谷呼吸性窦性心律不齐或高频功率（pvRSA/HF）。此外，中风（STROKE）及其亚型：缺血性中风（IS）、心源性栓塞性中风（CES）、小血管中风（SVS）、大动脉中风（LAS）、腔隙性中风（LS）和脑出血（ICH）也来自该数据库。采用两样本孟德尔随机化和各种敏感性分析来探讨HRV与中风及其亚型之间的因果关系。逆方差加权（IVW）是进行孟德尔随机化（MR）的主要方法，对于通过IVW确定的因果估计，进行了一系列敏感性分析以评估结果的可靠性。（i）使用了四种补充IVW的额外MR方法；（ii）采用 Cochr an's Q检验评估异质性；（iii）应用MR-Egger截距检验和MR-PRESSO全局检验评估多变量有效性水平，以及（iv）采用“留一法”评估稳定性。
HRV的两个遗传预测指标（正常心跳间期标准差[SDNN]）和（峰谷呼吸性窦性心律不齐或高频功率[pvRSA/HF]）与IS（比值比0.63，95%置信区间0.42 - 0.95，P = 0.03）、（比值比0.84，95%置信区间：0.72 - 1.00；P = 0.04）以及LAS（比值比135.93，95%置信区间：7.19 - 2569.22；P = 0.05）、（比值比1.42，95%置信区间：1.02 - 1.98；P = 0.04）显著相关，此外（pvRSA/HF）与LS（比值比0.84，95%置信区间：0.72 - 1.00；P = 0.04）也存在因果关联。两者均与中风的其他亚型或出血性中风无因果关联。HRV的另一个遗传预测指标（心跳间期连续差值的均方根[RMSSD]）未发现与中风、其亚型或脑出血有显著关联。
本研究提供了遗传证据，支持HRV（SDNN）对缺血性中风（IS）和大动脉中风（LAS）以及（pvRSA/HF）对缺血性中风（IS）、大动脉中风（LAS）和腔隙性中风（LS）的因果效应。
